Derivatives of dl-hexahydro-2-oxo-4-(4-haloakyl)-1-furo-(3, 4)-imidazole and process for preparing same



Patented May 9, 1950 DERIVATIVES OF DL-HEXAHYDRO-2-OXO-4- l-HALOALKYL) -1-FURO- (3,4) -IMIDAZOLE AND PROCESS FORPREPARING SAME Klaus Hofmann, Pittsburgh, Pa.., assignor to Ciba Pharmaceutical Products, Incorporated, Summit, N. J a corporation of New Jersey No Drawing. Application August 7, 1947, Serial No. 767,319

12 Claims.

The present invention relates to new and useful chemical compounds-certain furo-imidazole derivatives-which are more particularly characterized by a marked antibiotic activity.

with thionyl chloride, and the resulting chlorides may be converted (a) to the corresponding benzylthioethers by reaction with an alkali metal benzylmercaptide, such as sodiobenzylmercaptide, (b) to the corresponding mercaptoalkanols It has been found that compounds which cor- 5 respond to the structural formula by reaction with an alkali metal hydrosulfide, such as potassium hydrosulfide, and (c) to the 0 corresponding sulfonic acids by reaction with a an alkaline sulfite, such as ammonium sulfite. The benzylthioethers may, if desired, be con- 5 verted into the corresponding mercaptoalkanols I H by reduction with sodium and alcohol. The mermc CH-RR' captoalkanols may, in turn, be oxidized with permanganate to the corresponding sulfonic l5 acids. wherein R represents a lower polymethylene The foregoing may be schematically outlined group, and R represents a sulfhydryl group, a as follows:

H000 COOH H000 00011 0100 0001 r ROH R-OAc R-OAc \o/ O N160 CON: mooonN NHOOOR ROOOHN Nnooom \o/ ROAc 12-011 I o -R0H v i i i HN/ \N'H HN/ \N'H HN/ \NH R-0H R-hal R-SOHaUoE E Hit ml R-soua thiobenzyl ether group or a sulfonic acid group, are endowed with marked antibiotic activity and are capable of inhibiting the growth of micro-organisms.

The new compounds may be prepared from 3,4-dicarboxy-2-furan-alkano1s (see copending application Ser. No. 756,096, filed June 20, 1947) which are acetylated, esterified, converted by a modified Curtius degradation [3. A. C. S. 67, 1459 (1945)] into 3,4-dialkylcarboxyamino-2- furan-alkanols which, by catalytic hydrogenation and ring closure with barium hydroxide, are converted to the dl-hexahydro-2-oxo-4-alkanol- 1-furo-3,4-imidazoles.

R-SH

In the above scheme, hal stands for chlorine or bromine, and R stands for lower alkyl, such as ethyl, propyl, etc. While R is preferably one of (CH2)3 and -(CH2) 4, the invention is not thus limited and extends to compounds wherein R is any lower polymethylene group, i. e.-(CHz), where :0 may range from 2 to 6 or more.

The following examples illustrate methods of carrying out the invention, but it is to be understood that the examples are given by Way of illustration and not of limitation. The parts by Weight bear the same relation to parts by The latter are treated 545 volume as do grams to cubic centimeters.

Example 1 To a suspension of 30 parts by weight of 3,4-di- 7, rcarboxy-"2-f'uran butanol acetate .and' 150 parts by volume of dry-ether are added, in smallamounts, with cooling and shaking a total of 52 parts by weight of phosphorus pentachloride.

,Shaking is continued until most of the phosphorus pentachloride has disappeared and the ether is removed in vacuo at a bath tem erature of 40-45 C. 50 additional parts by volume of ether are added to the residue with subsequent? removal and this procedure is repeated twice more. The residue is dissolved in-300 parts by volume of ether and stirred vigorously in an ice weight of sodium azide and 75 parts by volume of water. '70 parts by volume of 40% potassium hydroxide are then added and stirring continued for another hour- The ether' layer is separated,

. the aqueous-layer re-extracted with freshether,

and the ether extracts dried over freshly dessicated sodium sulfate. The .dried solution is filtered through a fiutedfilter half filled with sodium sulfate and the ether is removed in :vacuo at a bath temperature of 20 C. The resulting oily 'azide is dissolved'in 300 parts :by'volnrne of vacuo, the residue diluted with water and ex-.

tracted withwether. The ether extracts are washed with 3 portions of 2 normal hydrochloric acid and 1 portion'of sodium bicarbonate, dried 'over sodium sulfate and the solvent evaporated on the steam bath. The resulting oily residue crystallizes on standing. The urethane crystals have a melting point of A solution of 10.8 parts by weight of the above urethane in 175 parts by volume of glacial acetic acid are hydrogenated at room temperature and atmospheric pressure in the presence of .22 parts by weight of a palladium-on-barium-sulfate.

catalyst until 2 mols. of hydrogen have been absorbed (reaction complete in'about 2 hours) The catalyst is removed by filtration, the glacial acetic acid is evaporated in vacuo, and 7.00 parts by volume of 10% barium hydroxide are added to the residue and the mixture heated to 90 -;C. with stirring for two hours. Carbon-dioxide is passed into the hot solution for approximately 30 minutes, the barium carbonate isifiltered out and '4 ride is then removed in vacuo'and the residue dissolved in a mixture of water andethyl acetate. The ethyl acetate layer is separated and washed removed on the steam bath nd the residue placed :in the refrigerator where crystallization soon 11-6 bath for 2 hours with a solution of 28 parts by.

occurs. The crystals are washed with ice cold ethyl acetate and recrystallized from the same solvent 'to yield dl-ehexahydro-2-oxo-4- l-chlorobutyl) -l-furo-(3,4) -imidazole melting at 124- To agsoltuion of 0.442 part by weight of the above chloride in 10 parts by volume of absolute alcohol, 1.1 parts by volume of a sodiobenzylmercaptide solution prepared by dissolving 1.2 parts by Weight of sodium in a'mixture of 19 parts by volume of absolute alcohol and 6 parts by volume of benzylmercaptanare added and the mixture ,refiuxedfor twoihours. The alcohol is removed in vacuo, theresidue dissolved inethy'l acetate, and the solution washed with several portionsof water, dried over sodium sulfate :and the ethyl acetate removed invacuo. .The oily residue solidifies on standing and the crystalsare washed with ether and purified by recrystallization in dilute methanol. dl-hexahydro-2-oxo-4- l-benzylthiobutyl) -1-fur,o- (3,4) -imidazole is obtained in the form of silky needles melting at YB-79 C.

To 4 parts by weight of sodium in a round bottomed fresh, 9. solution of 0.5 part by weight of the above thioether in parts by volume of ab- QIut a cQhQ is ,a d dratpnc nd th ure r fluxed until all f. thelsodium has dissolved- 200parts'by volume of absolute alcohol are then I added and carbon dioxide passed into the solution for one hour. The sodium carbonate is reabove thiobutanolin 39,parts by volume of water the solution evaporated to'dryness in vacuo. The

residue isextra'cted with *three portions of 150 parts by volume each, of boiling =dioxane which are combined, filtered and .conciotrated -to a small volume; 0n cooling, dl-hexahydro..-'2oxo- 4--'(4- hydroxybutyl) 1 --furo- (3,4 Amidazole :is ob tained, which when recrystallized from dioxane 7 melts at 154-'156 C.

2 parts by weight of the above butanol are placed in a round bottomed flask surrounded with ice and 5 parts-by volume of ice-cold thiony'lchloride are "added at once. The butanol dissolves Within a few minutes and the solution is removed from the icebath and keptiat roomtemperature V for approximately-1'2 "hours; The thionylchlowhich-is'cooled in an ice bath, a 0.01 molar solution of barium permanganate is added slowly with stirring-until the pink {color remains for 20 minutes. (Approximately H4 parts by volume of the solution are required), The mixture is heated on the steam bath and .2 parts by volume of methanol are added in iOI'del' to decompose the excess permanganate. The manganese dioxide is removed by filtration and the clear filtrate concentrated to idrynessin vacuo. The crystalline residue is-suspended in hot 95% ethyl alcohol and water is added until -allthe barium :salt has 1) are added and the mixture refluxed for two hours. The benzylthioether is isolated as described in Example 1. Recrystallization from dilute methanol yields needles melting at 66-68 C.

0.500 part by weight of the above thioether are cleaved with sodium in absolute alcohol as described in Example 1 to yield the mercaptide of melting point 92-94 C.

To an ice-cold solution of 0.200 part by weight of the above thiopentanol in parts by volume of water and one part by volume of acetone, a 0.01 molar solution of barium permanganate is slowly added with stirring until the solution remains pink for 30 minutes (approximately '76 parts by volume). The excess of permanganate is destroyed by the addition of 2 parts by volume of methanol and heating on the steam bath, and the solution filtered and concentrated to dryness in vacuo. The residue is dissolved in a small amount of water, acetone is added until the solution becomes cloudy and the barium salt of the sulfonic acid crystallizes out. dl-hexahydro-Z- oxo-1-furo-(3,4) -imidazole 4-(pentane sulfonic acid) is obtained in the form of the barium salt which is purified by recrystallization from dilute acetone.

Example 3 0.5 part by weight of potassium is dissolved in 25 parts by volume of absolute ethanol and converted to the hydrosulfide by passing in hydrogen sulfide. While refiuxing on the water bath and continuing to pass in hydrogen sulfide a solution of 2.2 parts by weight of dl-hexahydro-2- oxol-( -chlorobutyl) -1-furo (3,4) imidazole dissolved in 30 parts by volume of absolute ethanol is added slowly. The mixture is heated for an additional 20 minutes after all the chloride is added. Most of the alcohol is removed'in vacuo. To the residue is added 20 parts by volume of water and the solid material filtered off and washed with water in an atmosphere of carbon dioxide. The product, dl-hexahydro-2- oxo-4-(4'-mercaptobutyl)-1-furo (3,4) imidazole, is recrystallized from ethyl acetate.

Example 4 1.1 parts by weight of dl-hexahydro-2-oxo-4- (4'-chlorobutyl) -l-furo- (3,4) -imidazole and 1.4 parts by weight of ammonium sulfite and 100 parts by volume of 80% ethanol are heated on the steam bath for 3 hours. A solution of 3.15 parts by weight of barium hydroxide in 100 parts by volume of warm water is added and the barium sulfite precipitate filtered oil. The filtrate is evaporated to dryness and the barium salt of the sulfonic acid crystallized from dilute ethanol.

In those cases where the sulfonic acid is obtained in the form of the barium salt, the free sulfonic acid can be obtained, if desired, by dissolving the barium salt in water, exactly precipitating the barum ion with sulphuric acid, filtering off the precipitated barium sulfate and evaporating the filtrate to dryness.

Having thus disclosed the invention, what is claimed is:

1. A compound of the formula t HN/ \NH wherein X is a member selected from the group 6 consisting of SCI-I2CeI-I5, SH and SOaH, and E is a lower polymethylene group. 2. A compound of the formula wherein R is a lower polymethylene group.

3. A compound of the formula {IR-SH wherein R is a lower polymethylene group.

4. A compound of the formula NN NH wherein R is \8, lower {polymethylene group.

5. The compound of the formula t HN NH 6. The compound of the formula 7. The compound of the formula 8. In a process for the preparation of an oxybiotin derivative containing sulfur in the side chain of the oxybiotin molecule, the step of reacting a compound of the formula containing radical and selected from the group 7 consisting of alkali metal benzylmercaptida'ammonium sulfite and potassium hydrosulfide.

9. In a processfor the preparation of an oxybiotin derivative containing sulfur in the side chain of the oxybiotin molecule, the step of reacting a compound of the formula O V HN/ \NH 7 wherein R is a lower polymeth'ylene group, with soidobenzylmerclaptide to produce the corresponding benzylthioether.

11.111 a" process: for the preparation of an 7 oxybiotin derivative containing sulfur in the side chain. of the oxybiotinrmolecule, the step of reacting a compound of the formula E V HN/ \NH R-Ol wherein R a lower 'polymethylene group, with ammonium sulfite to produce the corresponding sulfonic acid. 7 Y

12. In a process for the preparation of an oxybiotin derivative containing sulfur in the side chain of the oxybiotin molecule, the step of reacting a compound of the formula V O R-Cl wherein R is a lower polymethylene group, with potassium 'hydrosulfide to produce the corresponding mercamtoalkano V KLAUS HOFMANN.

No references cited.

Certificate of Correction Patent N 0. 2,506,594

May 9, 1950 KLAUS HOFMANN It is hereby certified that errors appear in t numbered patent re he printed specification of the above qulrmg correctlon as follows: Column 2, line 48, for the f ormula OH )-X; read -(OH )x" col line 64, for conecntrated read concentrated; col solution; column 6, line 27 e 13, for soltuion read t at portlon of the formula reading N N read HN column 7, line 32, for soidobenzylmercaptide read sodiobenzylmercaptide; and that the said Letters Patent should be re e same may conform to the re ad with these corrections therein that cord of the case in the Patent Office. Signed and sealed this 5th day of September, A. D. 1950.

THOMAS F. MURPHY,

Assistant Gammz'ssz'oner of Patents. 

1. A COMPOUND OF THE FORMULA 